In this study, we investigated whether rIL-35 or single chain mouse IL12p35 protein can be used to treat CNS autoimmune diseases such as Uveitis or Multiple Sclerosis. These studies led to our identification a unique regulatory B cell (Breg) population that plays critical roles in regulating immunity during autoimmune diseases by secreting IL-10 and IL-35. Expansion of i35-Bregs during uveitis or encephalomyelitis in mice conferred protection from these CNS autoimmune diseases while mice lacking i35-Bregs or defective in IL-35-signaling pathway developed severe uveitis or encephalitis. Our discovery that IL-35 induces conversion of human B-cells into Bregs, suggests that ex-vivo generated Bregs can be exploited for adoptive immunotherapy in CNS autoimmune and neurodegenerative diseases.